This project seeks to improve the clinical care available to patients with disorders of ovarian follicle function. In pursuing this goal, we expect to expand basic science understanding of the ovarian follicle in health and disease. We have focused on premature ovarian failure, a condition that prematurely terminates normal ovarian function and fertility in 1% of women. We have particular interest in autoimmunity as a cause of ovarian failure. Our strategies to investigate the mechanisms of premature ovarian failure involve work in the clinic as well as in the basic science laboratory. For most young women with premature ovarian failure the most troubling part of the diagnosis is the associated infertility, and this is a major focus of our work. Nonetheless, young women with this condition have other needs that must be met by their health care providers. It is well established that patients with spontaneous premature ovarian failure are at increased risk of developing autoimmune adrenal insufficiency, a potentially fatal disorder. There has been ongoing controversy regarding the best clinical strategy by which to detect adrenal insufficiency at an early stage in these young women. We have demonstrated that the presence of anti-adrenal antibodies in the serum is highly associated with adrenal insufficiency while a negative test was associated with normal adrenal function in all cases. Our findings demonstrate that measuring adrenal antibodies is an effective screening method by which to detect asymptomatic autoimmune adrenal insufficiency in young women with spontaneous premature ovarian failure. Also, during the past year we found an association between ocular surface disease and premature ovarian failure that has not been reported before. Keratoconjunctivitis sicca is defined as at least one symptom of dry eye occurring often or present all of the time. There are two major mechanisms of keratoconjunctivitis defined on the basis of either aqueous tear deficiency or evaporative tear deficiency. A decreased volume of tear production characterizes aqueous tear deficiency, and may be the result of autoimmunity directed against the lacrimal glands. A qualitative disturbance in the tear film with resultant instability, leading to increased evaporation and dryness of the ocular surface, characterizes evaporative tear deficiency, and this is most frequently the result of meibomian gland disease. Meibomian gland dysfunction leads to decreased lipid production, which results in tear film instability. Interestingly, androgens, which are deficient in women with POF, appear to play an important role in supporting normal meibomian gland function. Compared with age-matched control women, we found that young women with 46,XX spontaneous premature ovarian failure have an increased prevalence and severity of both signs and symptoms of ocular surface disease. Given that not all patients had dry eye, it is possible that the dry eye phenotype may signal a particular mechanism of premature ovarian failure, such as autoimmunity, since not all patients had dry eye. It is also possible that endocrine factors, such as the androgen deficiency associated with POF, might explain the association. Additional studies are planned to further characterize this pathology and determine its etiology. In a mouse model, we found that autoantibodies from mice with experimental autoimmune oophoritis bind to Mater, a novel 125 kd protein that is specific to the oocyte cytoplasm. Mater is a novel oocyte-specific maternal effect gene whose product we previously demonstrated is essential for embryonic development beyond the two-cell stage. Recently we defined the human homologue of mouse Mater, a maternal effect gene critical to female fertility. The human and mouse cDNA share 67% homology while their deduced polypeptide chains have 53% identity of amino acids. Also, their proteins have a number of simiilar structures. Characterization of the human MATER gene and its protein provides a basis for investigating their clinical implications in autoimmune premature ovarian failure and infertility in women. We are now evaluating the antigenic role of Mater in a mouse model of autoimmune ovarian failure. Also, we have generated a mouse line lacking Mater and we are investigating this mouse as a model for human idiopathic infertility. During the past year we demonstrated that the expression pattern of Mater and its protein is consistent with its role as a maternal effect gene, and we also demonstrated by immunogold electron microscopy that Mater protein is localized in the nucleolus and mitochondria.